1. Field of the Invention
The present invention relates to novel biomaterials including treated chitosan compositions, modified chitosan compositions, modified and treated chitosan compositions, or mixtures or combinations thereof and to methods for making and using same.
More particularly, the present invention relates to novel biomaterials including treated chitosans, modified chitosans, modified and treated chitosans or mixtures or combinations thereof, where at least one chitosan has one or more physical, chemical, and/or performance properties or characteristics that distinguish the treated chitosan, the modified chitosan, or the modified and treated chitosan over similar compositions including corresponding untreated chitosan. The present invention also relates to adhesive compositions or systems including a chitosan composition of this invention, drug delivery compositions or systems including a chitosan composition of this invention, filler or bulking compositions or systems including a chitosan composition of this invention, and to methods for making and using the same.
2. Description of the Related Art
Competitive Adhesive Technologies
The search for an effective tissue adhesive has resulted in many products, all of which suffer from deficiencies.
The most common tissue adhesives currently on the market are fibrin sealant based products. In this system the components of the natural clotting factors, fibrinogen and thrombin, react mimicking the final stage of the body's natural clotting mechanism. The resulting fibrin clot or film adheres to tissues to stop bleeding and improve the wound healing. The bond strengths of these products are not sufficient to hold tissues in approximation without the use of mechanical closures such as staples or sutures.
Cyanoacrylate products have been used to close skin breaks in the United States. When applied to tissue, the cyanoacrylate monomer undergoes an exothermic hydroxylation reaction that results in polymerization of the adhesive. The biological alkyl chains can be modified to modulate the physiological response. The shorter-chain derivatives (methyl and ethyl) tend to have a higher degree of tissue toxicity than the longer-chain derivatives (2-octyl). Inflammation, tissue necrosis, granulation formation, and wound breakdown can occur when cyanoacrylates are implanted subcutaneously. The process causing the histological toxicity is thought to be related to the by-products of degradation, cyanoacetate and formaldehyde. The cured polymer is brittle and presents a barrier to tissue regrowth. The addition of plasticizers can provide a more flexible bonding substrate.
Natural proteins such as collagen and albumin can be cross-linked with aldehyde cross-linking agents producing a biologically based adhesive. Concerns such as the toxicity associated with the aldehyde component, complexity of use and irreproducible results have limited the acceptance by physicians. This type of adhesive was first approved with a humanitarian device exemption (HDE) but has seen some expansion of use both on and off label. The product is glutaraldehyde crosslinked bovine serum albumin (BSA). The presence of glutaraldehyde prohibits its contact with neural tissues, as it can cause acute nerve injury. This class of adhesive has also been shown to impair aortic growth and to cause anastomotic strictures, thereby precluding its use in children. In addition, the adhesive has a very rapid curing time causing frequent blockage in the dual chamber delivery syringe and resulting in inconsistent bonding efficacy. These associated difficulties or complications limit its effectiveness.
Natural proteins secreted by such organisms as mussels, or synthetic analogues, have been used as tissue adhesives. These technologies require the use of primers and polymerizing agents that are typically toxic, severely compromising their potential biocompatibility and safety. Synthetic polymers have been developed that center around engineered proteins that resemble collagen and elastin. Impressive bond strengths have been realized, see, e.g., U.S. Pat. No. 6,875,796, with materials that would appear to be biocompatible. In order to achieve these bond strengths, tissues are primed with materials, such as chloroform, that would not be compatible with tissues. In addition the matrix is strengthened through the addition of incompatible crosslinkers, dopes, and primers, such as glutaraldehyde, formaldehyde, 1,6-diisocyanatohexane, 4-isocyanatomethylphenyl-3-isocyantopropanate, resorcinol, Eosin Y and Eosin B. Similarly, a proposed class of dendritic materials also requires the added complexity and potential toxicity issues involved with the use of biologically incompatible primers.
Polyethylene glycol (PEG) products are on the market but their strength is fairly low, even with photopolymerization, and most products require mixing prior to use. Surgeon acceptance has apparently been slow even with the relative biological safety of the products.
Competitive Local Drug Delivery Technologies
Local drug delivery technology can be grouped by function. Sustained release technology seeks to deliver the active pharmaceutical over an extended time. Polymeric materials that physically entrap the drug may provide a means for providing passive delivery over a period of time. In addition, the polymeric materials can supply enhanced characteristics such as stability or solubility enhancement. The polymer matrix may be degraded, retrieved or left in place in the case of many implantable devices, at the end of the drug delivery cycle.
To increase the specificity of the local drug delivery, targeted delivery technologies seek to enhance the movement and/or release of the pharmaceutical agent(s) through the use of focused RF or ultrasound.
Enhanced absorption/transport technologies seek to increase the absorption of the drug by increasing the uptake by target tissues. This has been found to be especially effective when used in a mucosal environment.
In the above technologies, the drug is passively released or released on an external trigger, not as a response to metabolic state or excretion of metabolic products by cells comprising the tissues.
Competitive Filler or Bulking Technologies
Dermal fillers are typically produced from bovine collagen, hyaluronic acid, poly-lactic acid, or calcium hydroxyl-apatite. Dermal fillers are used to reduce or eliminate wrinkles, raise scar depressions, enhance lips or replace soft-tissue volume loss. Injection of fillers is usually accomplished using a small needle, the dermal filler is injected into each wrinkle or scar that requires treatment. Some initial discomfort and bruising is experienced but such side effects generally subside quite quickly. Side effects are uncommon but can include allergic reactions, ulceration, reactivation of herpes infection, bacterial infection, localized bruising, and granuloma formation. Movement or “beading” of the material is sometimes seen giving an unpleasing aesthetic result. The benefits resulting from the increase in volume generally lasts for three to six months for the biologically derived fillers, somewhat longer with the synthetic materials. Improvements in the longevity and performance of the filler materials, as well as a decrease in adverse side effects, are currently being sought by the industry.
Chitosan History
Chitosan is a cationic polysaccharide derived from the partial deacetylation of chitin from the exoskeleton of crustaceans, including shrimp, lobster, and crabs. Its chemical nature is best described as a deacylated-(1,4)-N-acetyl-D-glucosamine polymer. The adhesive nature of chitosan has been known for some time. However, to date, no adhesive product based on chitosan has been produced. This is due in large measure to the difficulties in handling chitosan and delivering it in a form that quickly bonds to tissue without associated problems due to high acid concentrations. According to a search on the USPTO database, only 14 patents have been filed with an abstract or claims containing chitosan and adhesive. Most of these patents are for the paper industry. U.S. Pat. No. 5,773,033 disclosed fibrinogen/chitosan hemostatic agents, but not for use in tissue bonding. U.S. Pat. No. 6,329,337 entitled “Adhesive for Biological Tissue” disclosed a glue agent produced from a recombinant human plasma protein and bifunctional or multifunctional aldehydes. Chitosan was used in the agent to enhance the viscosity of the solution or as a crosslinking reagent with bifunctional or multifunctional aldehydes. U.S. Pat. No. 5,496,872 disclosed chitosan in a fairly exhaustive list of potential reagents, but relies on thiols, carboxylic acids and radicals to bond. U.S. Pat. No. 6,200,595 disclosed a combination of polycationic substrates, including chitosan, along with polyanionic substrates to be used as a potential medical adhesive. Reported bond strengths in this patent did not exceed 70 g-f/cm2. Additionally, this invention requires mixing of two components immediately prior to use. U.S. Pat. No. 6,991,652 disclosed the use of chitosan as one in a list of many potential materials to be used as a matrix for cellular growth.
A survey of the literature revealed that dialysis of chitosan has been used as a purification step and as a means for introducing coadditives. For example, U.S. Pat. No. 6,310,188 utilizes dialysis of chitosan to remove low molecular weight compounds.
Although a number of systems have been considered for use in the arena of tissue adhesives, the currently available systems suffer from deficiencies including toxicity, insufficient strength, or difficulty in use. Thus, there is a need in the art for additional compositions that are safe and effective tissue adhesives that can be provided in a sterile and easy-to-use form. Such highly adherent compositions would also offer significant advantages in drug delivery. There is also a need in the art for compositions that remain highly hydrated offering novel fillers, bulking compositions, or reconstructive compositions for use in cosmetic and reconstructive surgical procedures.